Hepatitis B virus (HBV) is one of the world's most common infectious agents causing millions of infections each year [1]. Between 500,000 and 700,000 people die each year from chronic infection-related cirrhosis, hepatocellular carcinoma (HCC) or from fulminant hepatitis B [1,2]. Transmission occurs via percutaneous and mucosal exposure to infectious body fluids. Therefore, the most common route of transmission is sexual transmission. However, infection through blood transfusions and blood products has not been completely eliminated and contaminated injections during medical procedures, sharing of needles, syringes and paraphernalia among intravenous drug users still represent a major public health problem. Vertical transmission is common, especially in Asia and developing countries which have not implemented hepatitis B vaccination. Further, HBV poses a risk to healthcare workers exposed to accidental needle-stick injuries.
Hepatitis B vaccine is a vaccine developed for the prevention of hepatitis B virus infection. The vaccine contains one of the viral envelope proteins, hepatitis B surface antigen (HBsAg). It may be recombinantly produced in yeast cells, into which the genetic code for HBsAg has been inserted. Vaccination with Hepatitis B surface antigen (HBsAg) provides protection against HBV infection and prevents complications including liver cirrhosis and HCC. The control and the eventual elimination of HBV infection are possible with the appropriate use of hepatitis B vaccines, and this will reduce significantly the disease burden and its associated costs.
Although prevention of HBV infection may be effectively achieved by vaccination there are certain situations that require a different prophylactic approach. Liver transplantation for end-stage HBV-related liver disease is one such example. Hepatitis B immune globulin (HBIG) has played a central role in prophylaxis against recurrent hepatitis B in patients undergoing liver transplantation.
Prior to the routine use of HBIG as immunoprophylaxis, recurrence of HBV in the liver allograft occurred in up to 80%, and infrequently was associated with an aggressive fibrosing cholestatic variant that caused progressive graft dysfunction and significant mortality. The subsequent availability of safe and effective antiviral drugs led to additional survival benefits by improving prophylactic efficacy and preventing disease progression in those with recurrence [3].
HBIG is a polyclonal antibody to HBV surface antigen (HBsAg) derived from pooled human plasma. Although its mechanism of action is not yet completely understood, it is thought that HBIG acts in the circulation by preventing hepatocyte infection, binding to and neutralizing circulating virions expressing HBsAg and perhaps inducing lysis of infected cells [4]. Within the liver, HBIG may also prevent cell-to-cell infection as well as reduce HBsAg and virion secretion upon endocytosis into hepatocytes [5].
To provide maximal protection against re-infection of the liver graft, HBIG should be given frequently (typically daily) for the week following transplantation. The pivotal multicenter European trial demonstrated that long term administration of intravenous (IV) HBIG reduced hepatitis B recurrence rates from 75% to 36% and was associated with improved graft and patient survival [6]. Subsequent trials, using variable schedules for HBIG administration, confirmed the efficacy of HBIG as a monotherapy against recurrent HBV infection [7].
HBIG prophylaxis is expensive. HBIG are commonly administered intravenously at high dose, daily for the first week and monthly thereafter, which makes the current costs of management of patients transplanted for HBV-related cirrhosis prohibitive, even for developed countries. Dose reduction has been proposed for cost reduction, either based on a flat dose or on a response-guided basis in order to maintain circulating anti-HBs at a protective level. However, HBIG doses are variable and should be individualized among patients. It has also been proposed to abandon HBIG prophylaxis in favor of using antiviral drugs alone, however this is a very controversial issue [3].
The cost of HBIG treatment and prevention are not the only limitations to its use. Additional limitations include the following: i) supply is limited and depend on vaccinated human donors exhibiting high titer protective anti-HBs, ii) purification is time consuming and must undergo lengthy virus-inactivation procedures; iii) anti-HBs titer is variable and effective virus neutralization efficiency largely unknown being exclusively based on arbitrarily protective anti-HBs serum titers; iv) polyclonal immunoglobulin include several antibody specificities and may select for HBV mutants resistant to currently available antiviral drugs; v) HBIG preparations are currently combined with antiviral drugs to insure complete protection, thus adding to the costs.
In conclusion, there is an unmet medical need for a sustainable reagent allowing standardization of immunoprophylaxis of HBV re-infection in the liver transplant. Such a standardized reagent could then also beneficially be used in other settings, such as in the acute treatment of accidental needle-sticks and in the prevention of vertical, perinatal HBV transmission. Administration of anti-HBs antibodies is usually performed as a prophylactic measure while waiting for the full development of vaccine-induced adaptive immunity to HBV.
Monoclonal antibodies have been proposed and developed in order to address that need. Most monoclonal antibodies against HBV are of murine origin. Such murine antibodies have the inherent disadvantage that they evoke an immune reaction in a human recipient when used in a therapeutic or prophylactic composition.
Human monoclonal antibodies capable of neutralizing HBV infection have also been described.
WO 2011/045079 describes the isolation and characterization of 2D028, a monoclonal antibody specific for the large pre-S1 HBV envelope protein. The antibody reacts with an epitope slightly downstream of the N-terminus of pre-S1 (amino acids 21-47). It is stated at paragraph [00105] of WO 2011/045079 that HBV infection was essentially undetectable at 10 micrograms per milliliter of the antibody.
Another set of monoclonal antibodies termed HBV-17 and HBV-19 were described in Eren et al., Hepatology 32 (2000), 588-596. These antibodies had a specific activity of 514 IU/mg and 2,900 IU/mg respectively, as described on page 590, bottom of left column of Eren et al., Hepatology 32 (2000), 588-596.
Yet another series of human monoclonal antibodies has been described in Tajiri et al., Antiviral Research 87 (2010) 40-49. These antibodies did not seem to provide full protection against HBV infection, even not at the highest concentrations tested. FIG. 4 in Tajiri et al., Antiviral Research 87 (2010) 40-49 shows that there is still residual activity after neutralization of HBV with each of the antibodies tested.
Human monoclonal antibody HB-C7A has been described in Shin et al., Antiviral Research 75 (2007); 113-120. This antibody was capable of fully preventing HBV infection in two chimpanzees after mixing 100 CID50 of HBV and 100 microgram of HB-C7A. The antibody is said to have a titer of 2600 units per mg of antibody.
Despite of this progress in the art, there is a desire for more potent human monoclonal antibodies in order to cure or prevent HBV infection in humans more efficiently and effectively.